Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates energy balance. In diabetic rodents and monkeys, FGF21 has broad metabolic effects that include reducing serum glucose and triglyceride concentrations. We recently discovered that FGF21 expression is markedly induced in liver by peroxisome proliferator-activated receptor (PPAR), a member of the nuclear steroid/thyroid hormone receptor family that is activated by fatty acids. PPAR plays a central role in the fasting response, including the induction of fatty acid catabolism and ketogenesis, and is the molecular target for the fibrate class of dyslipidemia drugs. We have found that administration of recombinant FGF21 to mice recapitulates many of the metabolic actions of PPAR activation including the reduction of circulating triglyceride concentrations and the induction of ketogenesis. In addition, FGF21 reduces physical activity and enhances torpor, an energyconserving state of regulated hypothermia. Based on these data, we hypothesize that FGF21 is a fastinginduced hepatokine that coordinately regulates systemic metabolism and behavior to conserve energy. The studies outlined in this application are designed to directly test specific components of this hypothesis. In Specific Aim 1, we will examine the role of FGF21 in mediating the physiologic responses to PPAR agonists, fasting and high fat diets. In Specific Aim 2, the role of FGF21 in the induction of hepatic lipolysis and ketogenesis will be studied. In Specific Aim 3, we will examine whether the effects of FGF21 on torpor and activity are mediated via the central nervous system. We believe that these studies will provide important insights into the molecular mechanisms governing metabolism and will also yield unexpected insights into the molecular actions of the fibrate class of drugs. Ultimately, manipulation of the FGF21 signaling pathway may provide novel strategies for treating obesity, diabetes, and the metabolic syndrome.